Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments

Pippa Kennedy; Upasana S Arvindam; Shee Kwan Phung; Brianna Ettestad; Xueyang Feng; Yunmin Li; Quinlan M. Kile; Peter Hinderlie; Melissa Khaw; Rih Sheng Huang; Marissa Kaufman; Patrycja Puchalska; Amanda Russell; Jonah Butler; Lucas Abbott; Paul McClure; Xianghua Luo; Quynhanh T. Lu; Bruce R Blazar; Peter Crawford; James Lim; Jeffrey S Miller; Martin Felices

doi:10.1126/sciadv.adn1849

Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments

Pippa Kennedy, Upasana S Arvindam, Shee Kwan Phung, Brianna Ettestad, Xueyang Feng, Yunmin Li, Quinlan M. Kile, Peter Hinderlie, Melissa Khaw, Rih Sheng Huang, Marissa Kaufman, Patrycja Puchalska, Amanda Russell, Jonah Butler, Lucas Abbott, Paul McClure, Xianghua Luo, Quynhanh T. Lu, Bruce R Blazar, Peter CrawfordJames Lim, Jeffrey S Miller, Martin Felices

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Abstract

Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.

Original language	English (US)
Article number	eadn1849
Journal	Science Advances
Volume	10
Issue number	44
DOIs	https://doi.org/10.1126/sciadv.adn1849
State	Published - Nov 1 2024

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© 2024 American Association for the Advancement of Science. All rights reserved.

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Kennedy, P., Arvindam, U. S., Phung, S. K., Ettestad, B., Feng, X., Li, Y., Kile, Q. M., Hinderlie, P., Khaw, M., Huang, R. S., Kaufman, M., Puchalska, P., Russell, A., Butler, J., Abbott, L., McClure, P., Luo, X., Lu, Q. T., Blazar, B. R., ... Felices, M. (2024). Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments. Science Advances, 10(44), Article eadn1849. https://doi.org/10.1126/sciadv.adn1849

Kennedy, P, Arvindam, US, Phung, SK, Ettestad, B, Feng, X, Li, Y, Kile, QM, Hinderlie, P , Khaw, M, Huang, RS, Kaufman, M, Puchalska, P, Russell, A, Butler, J, Abbott, L, McClure, P, Luo, X, Lu, QT, Blazar, BR , Crawford, P, Lim, J, Miller, JS & Felices, M 2024, 'Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments', Science Advances, vol. 10, no. 44, eadn1849. https://doi.org/10.1126/sciadv.adn1849

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abstract = "Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.",

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AU - Feng, Xueyang

AU - Li, Yunmin

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AU - Huang, Rih Sheng

AU - Kaufman, Marissa

AU - Puchalska, Patrycja

AU - Russell, Amanda

AU - Butler, Jonah

AU - Abbott, Lucas

AU - McClure, Paul

AU - Luo, Xianghua

AU - Lu, Quynhanh T.

AU - Blazar, Bruce R

AU - Crawford, Peter

AU - Lim, James

AU - Miller, Jeffrey S

AU - Felices, Martin

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N2 - Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.

AB - Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.

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Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments

Abstract

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